Xanthine has the general structure: ##STR1## wherein R.sub.1, R.sub.2, R.sub.3, & R.sub.4 are each H. Xanthine compounds are referred to herein as compounds wherein R.sub.1, R.sub.2, R.sub.3, & R.sub.4 are independently selected from the group of moieties consisting of a hydrogen, an alkyl, an alkenyl, an alkynyl, an alkoxy, an amino, an aryl, a cycloalkyl, a hydroxy, a halogen, and a nitro.
Well known xanthine compounds include theophylline (1,3-dimethyl xanthine; i.e., R.sub.1 and R.sub.2 are CH.sub.3 and R.sub.3 and R.sub.4 are H in the general structure above), theobromine (3,7-dimethyl xanthine; i.e., R.sub.2 and R.sub.3 are CH.sub.3 and R.sub.1 and R.sub.4 are H in the general structure above). Of particular interest to the present invention, are compounds wherein at least two of R.sub.1, R.sub.2, and R.sub.3 are each independently a C.sub.1 -C.sub.4 lower alkyl, including but not limited to the dimethyl and trimethyl substituted forms, such as 1,7-dimethyl xanthine, and 1,3,7-trimethyl xanthine, as well as 8-substituted compounds (e.g., 1,3-dimethyl, 8-phenyl xanthine). For example, xanthine compounds include theophylline and derivatives thereof, including pharmaceutically acceptable salts thereof. Since the aqueous solubility of xanthine compounds tends to be low, reference to xanthine and xanthine compounds referred to herein also includes water soluble derivatives and complexes thereof. For example, the term theophylline includes the water soluble compound aminophylline, which is formed by the combination of theophylline with ethylenediamine (2:1).
The present invention arose from the need to find drugs which will counteract the intended effects and/or side-effects of other useful drugs. For the purpose of facilitating the description of the present invention, it is important to appreciate that, despite advances in understanding the molecular basis of drug actions, such as drug-receptor interactions, the mechanisms of action of many drugs that are presently used is not clearly understood. Thus, the difficulty in characterizing the biochemical actions of the drugs in complex physiological systems makes it extremely difficult to develop pharmacologic antagonists to counteract their intended effects and/or side-effects. Furthermore, when drugs with similar pharmacologic effects are administered concurrently, an additive or synergistic response is frequently seen, thereby compounding the problem in antagonizing the effects of the administered drugs. Hence, despite the long felt and great need to develop drugs to counteract the intended effects and/or undesired side-effects of drugs administered for useful purposes, there are few antagonists which enable a physician to achieve a desired effect with one drug, and to reverse an intended effect and/or undesired side effects with another drug. This need is particularly strong in the field of anesthesia.
For example, opioids are very useful drugs for analgesia and for producing anesthesia, but unfortunately can cause serious side effects including respiratory depression and arrest, which may cause hypoxia and death at high dosages. The drug naloxone has been found to counteract the respiratory depression effects of opioids, but also reverses the desired beneficial effects, namely analgesia. It is believed that naloxone competitively binds to opioid receptors.
Because of the inherent toxic and dangerous actions that certain drugs have and their low therapeutic ratio (toxic dose/therapeutic dose), there is a need for an antagonist drug to reverse or antagonize the dangerous and/or undesired effects of an administered drug, shorten the duration of the effects of an administered drug, and/or attenuate some or all of the effects of an administered drug. This is particularly true for drugs used in producing anesthesia for surgery or other purposes, wherein numerous drugs are concurrently administered to induce and/or maintain the variety of effects constituting anesthesia.
General anesthesia usually includes analgesia, hypnosis (sedation, amnesia, loss of consciousness), inhibition of sensory and autonomic reflexes, and, in many cases, skeletal muscle relaxation. An ideal combination of drugs for anesthesia would induce anesthesia smoothly and rapidly, and permit rapid recovery as soon as the administration of the drugs is ceased. Some of the drugs used in anesthesia have specific antagonists. Naloxone is used to antagonize opioid effects, flumazenil is used to antagonize benzodiazepines and neostigmine antagonizes the effects of muscle relaxants. However, there are no known antagonists to reverse the anesthetic effects of the inhaled anesthetics, or certain other classes of drugs useful in producing anesthesia, including propofol, barbiturates, etomidate, and certain purine compounds recently discovered to be useful in producing anesthesia. Thus, while naloxone reverses the effects of opioids, flumazenil reverses the effects of benzodiazepines and neostigmine reverses the effects of certain muscle relaxants, these drugs do not work to reverse the effects of other classes of drugs concurrently used in producing effects required for anesthesia, including surgical anesthesia. This illustrates the unpredictable nature of anesthetic drugs, and the difficulty of finding antagonist drugs, which can be safely used to counteract the effects of the various drugs used in the practice of modern anesthesia.
A major concern of anesthesiology is recovery from anesthesia. Most drugs used in anesthesia acutely depress the central nervous system (CNS) and inhibit protective reflexes (i.e., disrupt homeostasis and inhibit physiological functions required to live). In addition, the drugs that produce anesthesia also produce potent autonomic nervous system (ANS) side effects. The vital signs that an anesthesiologist usually monitors continuously during anesthesia often reflects ANS function and homeostasis. The use of potent anesthetics modifies the actions of a patient's body regulating functions, therefore, it is important to restore those physiological functions as soon as the need for anesthesia ends. Ideally, anesthesia is a totally reversible process, and most of the anesthetic agents currently used are relatively short-acting and safe. However, failure to promptly recover from anesthesia is always a major concern.
In modern anesthesia practice, the anesthetist is faced with challenges to the health of the patient due to the potent drugs used during the course of anesthesia. Thus, there is an urgent need for agents that will ensure that the side effects or toxicity of the potent drugs used to produce anesthesia are quickly counteracted at the end of the anesthetic procedure, and/or that the effects are shortened after surgery and anesthesia. Thus, it is desirable that the time for initial awakening, orientation and return of normal psychomotor performance be as short as possible after anesthesia. Most importantly, the quickest possible return of the patient's homeostatic mechanisms is a primary goal following any anesthetic procedure.
Anesthetics produce significant changes in mental function, which persist beyond the period of the anesthetic administration and the immediate postoperative period. Following prolonged anesthesia, subjects exhibit decreased intellectual function and increased incidence of subjective symptoms. Furthermore, it has been recognized in general that anesthetics, particularly the inhaled anesthetics and propofol, produce significant cardio-respiratory depression, which is dose-related. Therefore, there is a need for a drug and/or drugs to counteract and or shorten the CNS side effects of drugs used to produce anesthesia, including effects which persist postoperatively, such as obliviousness, inhibition, depression, and/or limitation of cognitive functions. The need also exists for a method to improve the recovery of psychomotor function after anesthesia is ended. A need exists for shorter recovery times, which could result in less health care costs by reducing the requirement for recovery room nurses, and special monitoring in the postanesthesia care unit. A further need exists for a general method to hasten recovery of respiratory and cardiovascular functions after anesthesia.